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Review
. 2021 Mar 29:15:654078.
doi: 10.3389/fnins.2021.654078. eCollection 2021.

The Neurobiology of Zika Virus: New Models, New Challenges

Luciana Monteiro Moura  1 , Vinicius Leati de Rossi Ferreira  1 , Rafael Maffei Loureiro  1 , Joselisa Péres Queiroz de Paiva  1 , Rafaela Rosa-Ribeiro  1 , Edson Amaro Jr  1 , Milena Botelho Pereira Soares  2   3 , Birajara Soares Machado  1
Affiliations
Review

The Neurobiology of Zika Virus: New Models, New Challenges

Luciana Monteiro Moura et al. Front Neurosci. .

Abstract

The Zika virus (ZIKV) attracted attention due to one striking characteristic: the ability to cross the placental barrier and infect the fetus, possibly causing severe neurodevelopmental disruptions included in the Congenital Zika Syndrome (CZS). Few years after the epidemic, the CZS incidence has begun to decline. However, how ZIKV causes a diversity of outcomes is far from being understood. This is probably driven by a chain of complex events that relies on the interaction between ZIKV and environmental and physiological variables. In this review, we address open questions that might lead to an ill-defined diagnosis of CZS. This inaccuracy underestimates a large spectrum of apparent normocephalic cases that remain underdiagnosed, comprising several subtle brain abnormalities frequently masked by a normal head circumference. Therefore, new models using neuroimaging and artificial intelligence are needed to improve our understanding of the neurobiology of ZIKV and its true impact in neurodevelopment.

Keywords: Zika virus; artificial intelligence; brain abnormalities; cell death; congenital Zika syndrome; neurodevelopment; neuroimaging.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Although ZIKV is well established as the cause of the CZS, the spectrum of outcomes is highly variable. (A) Depicts a schematic diagram of prenatal exposure to multiple variables. In this period, time-varying events and covariates hamper the precision in predicting the outcome, for which artificial intelligence (AI) algorithms may be crucial. The most important event is the timeline of the infection: presumably the earlier is the infection, the worse are the impairments. However, many other variables and possible confounders are present, such as: the viral lineage and the mechanism of infection; overlapping infections of other flaviviruses that might lead to an antibody-dependent enhancement (ADE); misdiagnosis due to surveillance pitfalls or intrinsic diagnostic difficulties; immune-response of the mother (including placental health) and fetus. In addition, four examples of the CZS spectrum are represented in radar charts (axes with arbitrary values). Alterations driving the different phenotypes are grouped and oversimplified. (B) Is the pentagon, a typical and severe case which is readily detected, not necessarily diagnosed due to a possible lack of laboratorial confirmation. The other phenotypes are frequently neglected: (C) represents less severe cases (in comparison to the typical one), though noticeable, in the lack of laboratorial confirmation it might depend on the monitoring; (D) represents the pseudo-normocephalic cases, clinical alterations and neuroimaging may be crucial; (E) represents mild cases with subtle alterations within the gray and/or white matter, which are particularly challenging to detect and consequently the most neglected.
FIGURE 2
FIGURE 2
Evolution of diagnostic criterion based on head circumference (HC) between 2015 and 2016 in Brazil (the epicenter of cases). Before the first wave of cases, HC cutoff was more restrictive (<30.7 cm for males and <30.3 cm for females), from Nov 17th, 2015 when the epidemic was clearly established the cutoff was altered to ≤33 cm for both sexes in the attempt to track new cases. This lack of distinction between sexes was kept up to March 12th, 2016, which might have overestimated particularly female cases.
FIGURE 3
FIGURE 3
(A) Schematic representation of the embryonic layers in the typical developing neuroepithelium is depicted in colors, proportional intervals in the timeline were not respected. ED – embryonic days; GW – gestation week; Cth – cortical thickness; VZ – ventricular zone, PP – preplate, SVZ – subventricular zone, IZ – intermediate zone, SP – subplate, CP – cortical plate, MZ – marginal zone, OSVZ – outer subventricular zone, ISVZ – inner subventricular zone. Discontinuous scaffolding is a singular pattern of migration that splits SVZ into two discontinuous layers; OSVZ is supposed to drive the tangential or radial expansion of the human brain through the outer radial glia cells. *Considering the maturation of the membranes; ** referring to the neurogenesis waves in the whole brain, though some regions, i.e., hippocampus keeps active processes of neurogenesis in the adult life. (B) Some key events that may occur are represented in the timeline of prenatal neurodevelopment after ZIKV infection. These events depend not only on the period of the infection but also on the many covariates. Therefore, the severity of findings in CZS is highly variable.
FIGURE 4
FIGURE 4
A few schematic examples of possible combinations of brain abnormalities in the CZS. There are two types of abnormalities: those that can be easily identified by the traditional imaging scans, such as calcifications and ventriculomegaly in CT scans; subtle alterations that are difficult to trace, requiring specific MRI sequences (frequently investigated in the scope of research). Scheme (A,B) depicts two typical images, normal developing and microcephalic brain, respectively. Schemes (C,D) depicts migration cortical abnormalities, such as pachygyria and polymicrogyria, better investigated by specific structural MRI sequences. Case (E) depicts a normocephalic case with subtle abnormalities in the white matter, better investigated by diffusion MRI techniques.
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